Chronic allograft injury is the leading cause of graft loss in renal transplantation. The shortage of available kidneys for transplantation has reached crisis levels with increasing numbers of waiting list mortalities. Strategies to prolong graft survival are urgently needed. The pediatric and young adult transplant population is one in which repeat transplantation is inevitable and therefore, this group is one who will especially benefit from intervention to prolong graft survival. Chronic allograft injury has replaced acute rejection as the major cause of graft loss. The potent immunosuppressive therapy that successfully reduced acute rejection rates has resulted in a higher incidence of infection due to herpes viruses, such as cytomegalovirus (CMV) and Epstein- Barr virus (EBV). Our prospective observational study in pediatric renal transplant patients demonstrated that subclinical CMV and EBV viral infection are associated with chronic allograft injury. We demonstrated that both high titers and prolonged episodes of subclinical CMV and EBV viremia are common despite oral antiviral therapy, and are independently and quantitatively associated with decreased GFR and histologic evidence of chronic allograft injury at two years'post-transplantation. These findings suggest that prevention, prophylaxis and/or treatment strategies targeting subclinical viral infection may be able to reduce the burden of allograft injury and associated graft loss in renal transplant patients. However, to guide such strategies the underlying link between subclinical viral infection and renal allograft injury must first be determined - including whether subclinical viral infection directly or indirectly contributes to allograft injury. To answer this question, we propose in Specific Aim 1 to prospectively determine the association of subclinical viral infection with renal allograft injury determined by;1) measured GFR (iohexol), 2) quantification of allograft fibrosis and 3) innate immune activation in the renal allograft. In Specific Aim 2, we propose to determine whether the presence of viral specific T cell immune responses - which are able to modify either mechanism of virus-associated injury - alter the time course of viremia and/or allograft viral infection, and allograft injury. PUBLIC HEALTH RELEVANCE: This is a 2 year study in pediatric and young adult kidney transplant recipients to evaluate how viral infections lead to damage and accelerated failure of kidney transplants.